This invention relates to the use of fractions of an extract of a Chinese herb in treating hyperglycemia.
The monosaccharide carbohydrate glucose is present in the blood of animals. It is the body's primary source of energy for cell metabolism, and it comes principally from the digestion of other carbohydrates. Despite wide variations in carbohydrate intake, and consequent large fluctuations in the amount of glucose absorbed by the body, the concentration of glucose in the blood, commonly referred to as the blood sugar level, is normally kept within narrow limits. In humans fasting blood glucose concentrations are considered normal if between 70 mg/dl and 114 mg/dl.
The maintenance of normal blood sugar levels is achieved by the actions of several hormones, most notably insulin, but also glucagon, epinephrine, corticosteroids, and growth hormone. Hypoglycemia, or low blood sugar, is characterized by below normal levels of blood glucose. On the other hand, hyperglycemia is exemplified by higher than normal concentrations of glucose in the blood. A substance which functions to decrease blood glucose levels is said to exhibit a hypoglycemic effect. Such a substance is sometimes called a hypoglycemic agent.
The pancreas produces insulin which is released in response to increased blood glucose concentrations. Insulin works to lower the blood sugar level by stimulating the uptake of glucose by cells. Glucose is either used in cellular metabolism to produce energy, converted to glycogen for storage in the liver and muscles, or used in the production of triglycerides and fats. As opposed to insulin, glucagon, epinephrine and corticosteroids all operate to increase blood glucose concentrations.
Many persons are afflicted with one of a genetically and clinically heterogeneous group of disorders that have glucose intolerance (hyperglycemia) in common. A good synopsis of these disorders is contained in The Merck Manual of Diagnosis and Therapy (Robert Berkow et al. eds., 16th ed., 1992). Impaired glucose tolerance, gestational diabetes and diabetes mellitus are diagnosed according to plasma glucose values in mg/dl. The National Diabetes Data Group has established the following criteria for classifying these illnesses.
TABLE 1 __________________________________________________________________________ DIAGNOSTIC CRITERIA OF THE NATIONAL DIABETES DATA GROUP Criteria for Diagnosis of Diabetes Mellitus and Criteria for Diagnosis Impaired Glucose Tolerance of Gestational (All plasma glucose values in mg/dL) Diabetes Impaired Glucose (100 gm OGTT) Normal Diabetes Mellitus Tolerance Venous Plasma Adult Child Adult Child Adult Child Glucose __________________________________________________________________________ FPG &lt;115 &lt;130 .gtoreq.140 .gtoreq.140 115-139 130-139 Fasting .gtoreq. 105 mg/dL OGTT &lt;140 &lt;140 .gtoreq.200 .gtoreq.200 140-199 140-199 1h .gtoreq. 190 mg/dL 2h .gtoreq. 165 mg/dL 3h .gtoreq. 145 mg/dL __________________________________________________________________________ FPG = fasting plasma glucose; OGTT = oral glucose tolerance test (at least 2 values). From Harris M., et al for the National Diabetes Group: "Classification an diagnosis of diabetes mellitus and other categories of glucose intolerance." Diabetes 28:1049, 1979. Copyright 1979 by American Diabetes Association, Inc.
The most well known of these disorders is diabetes mellitus. Diabetes mellitus is characterized by hyperglycemia resulting from impaired insulin secretion and is associated with a host of late complications including retinopathy, nephropathy, atherosclerotic coronary and peripheral arterial disease, and peripheral and autonomic neuropathies. There are two main types of diabetes mellitus. In Type I, or insulin dependent diabetes (also known as juvenile diabetes), the insulin-secreting cells in the pancreas are destroyed and insulin production ceases almost completely. Type II, or non-insulin-dependent diabetes (adult-onset diabetes), is usually marked by gradual onset wherein insulin is produced, but not in sufficient quantity to fully metabolize blood glucose. Both types result in an abnormally high level of glucose in the blood, which, if left uncorrected, can cause coma and death. In the United States alone about 150 to 200 persons per 100,000 have the insulin-dependent form of diabetes, while as many as 2,000 persons out of every 100,000 are affected with the more common Type II form.
There is good evidence that hyperglycemia conveys risks for all of the common late complications of diabetes mellitus, which are the major causes of excess morbidity and mortality in diabetics. However, there is no generally applicable and consistently effective means of maintaining normal plasma glucose fluctuations in diabetics, and efforts to do so entail significant risks of causing frequent or severe hypoglycemic episodes. Nevertheless, common treatments include diet management and the use of insulin preparations and oral hypoglycemic agents.
Insulin preparations are classified as short, intermediate or long-acting. Preparations of purified porcine insulin, purified bovine insulin, semisynthetic human insulin, and biosynthetic human insulin are now available. Conventional insulin treatment includes one or two injections per day of intermediate-acting insulin, with or without smaller added doses of rapid-acting insulin in the same syringe. Complications of insulin treatment include severe hypoglycemia, local allergic reactions, generalized insulin allergy, immunologic insulin resistance and local fat atrophy or hypertrophy.
Oral hypoglycemic agents are not used to treat insulin-dependent diabetes because they cannot prevent symptomatic hyperglycemia, but such agents can be effective when used in the treatment of non-insulin-dependent diabetes and other forms of glucose intolerance. Biguanides and sulfonylureas are the two historical classes of oral hypoglycemic agents. Biguanides, however, are not currently approved for treatment of diabetes in the United States. The sulfonylureas include tolbutamide, chlorpropamide, acetohexamide, tolazamide, glyburide and glipizide and lower plasma glucose by stimulating insulin secretion and also by enhancing insulin effect in some target tissues and inhibiting hepatic glucose synthesis. Authorities differ in the extent to which they recommend sulfonylureas. It is said that the sulfonylureas do not provide a rapid and consistently effective means of treating or preventing symptomatic hyperglycemia in patients with non-insulin-dependent diabetes, and in asymptomatic obese patients they are not consistently effective either in decreasing the hyperglycemia or in maintaining the commonly recommended target levels of plasma glucose. Hypoglycemia is the most important complication of sulfonylurea treatment. Sufonylurea-induced hypoglycemia can be severe and may last or recur for days after treatment is stopped. It is recommended that sulfonylurea-treated patients who develop hypoglycemia should be hospitalized and closely monitored, even if they respond rapidly to initial treatment for hypoglycemia, as a mortality rate of 4.3% in patients hospitalized with sulfonylurea-induced hypoglycemia has been reported.
Considering the complications attendant to the use of insulin preparations and sulfonylureas in controlling blood glucose concentrations, there is a need for a new composition and method for treating hyperglycemia that is useful in the control of the high blood glucose levels associated with glucose intolerance, but that utilizes an organically derived composition which is easy to manufacture and relatively inexpensive. Preferably the new composition would be useful in treating non-insulin-dependent hyperglycemia and would provide an alternative to the use of sulfonylureas.